Breast cancers exhibit genetic alterations representing an accumulation of mutations, failure of DNA repair, activation of oncogenes, and loss of tumor suppressor function [Osborne, C.; Wilson, P.; Tripathy, D. Oncologist 2004, 9, 361; Benson, J. R.; Liau, S. S. Surg. Clin. N. Am. 2008, 88, 681]. These genetic defects result in inappropriate intracellular signaling pathways that lead to the initiation, progression, and invasion of breast tumorigenesis [Visbal, A. P.; Lewis, M. T. Curr. Drug Targets. 2010, 11, 1103]. Breast cancer development may be associated with the presence or absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor-2 receptor (HER2) [Goldhirsch, A.; Ingle, J. N.; Gelber, R. D.; Coates, A. S.; Thürlimann, B.; Senn, H. J. Ann. Oncol. 2009, 20, 1319]. A positive receptor status is associated with favorable prognostic features and predicts response to hormonal therapy; however, this is balanced by a higher recurrence rate in subsequent years [Ellis, M. J. J. Natl. Cancer Inst. 2008, 100, 159; Abramson, V.; Arteaga, C. L. Clin. Cancer Res. 2011, 17, 952]. ER-, PR- and HER2-negative (triple-negative) breast cancers, which are poorly differentiated and generally fall into the basal subgroup of breast cancers, are significantly more aggressive [Rakha, E. A.; Tan, D. S.; Foulkes, W. D.; Ellis, I. O.; Tutt, A.; Nielsen, T. D.; Reis-Filho, J. S. Breast Cancer Res. 2007, 9, 404; Pal, S. K.; Childs, B. H.; Pegram, M. Breast Cancer Res. Treat. 2011, 125, 627]. Due to the absence of specific treatment guidelines for triple-negative breast cancers, they are managed with standard treatments; however, such treatments are associated with a high rate of local and systemic relapse [Cleator, S.; Heller, W.; Coombes, R. C. Lancet Oncol. 2007, 8, 235; Stockmans, G.; Deraedt, K.; Wildiers, H.; Moerman, P.; Paridaens, R. Curr. Opin. Oncol. 2008, 20, 614; Arslan, C.; Dizdar, O.; Altundag, K. Expert. Opin. Pharmacother. 2009, 10, 2081; Carey, L.; Winer, E.; Viale, G.; Cameron, D.; Gianni, L. Nat. Rev. Clin. Oncol. 2010, 7, 683].
ER, a transcription factor involved in the development and maintenance of female reproductive organs, drives the tumor growth in ˜70% of all cases [Greene, G. L.; Gilna, P.; Waterfield, M.; Baker, A.; Hort, Y.; Shine, J. Science 1986, 231, 1150]. Most chemotherapeutic anticancer drugs used in the clinical setup include anti-estrogenic agents that interfere with ER and prevent tumor progression [Nicholson, R. I.; Johnston, S. R. Breast Cancer Res. Treat. 2005, 93, S3; Regierer, A. C.; Wolters, R.; Kurzeder, C.; Wockel, A.; Novopashenny, I.; Possinger, K.; Wischnewsky, M. B.; Kreienberg, R. Breast Cancer Res. Treat. 2011, 128, 273]. Mitosis and other distinct pathways of apoptosis are considered as a potential target for the development of novel class of drugs that can overcome the limitations of current tubulin-targeted antimitotic drugs [Wood, K. W.; Cornwell, W. D.; Jackson, J. R. Curr Opin Pharmacol. 2001, 1,370]. Usually, normal cells avoid mitotic catastrophe by activating different cell cycle checkpoints, which allows them to repair the damage prior to entering mitosis. In contrast, cancer cells are mostly deficient in some of the cell cycle checkpoints [Shapiro, G. I.; Harper, J. W. J. Clin. Invest. 1999, 104, 1645; Blajeski, A. L.; Phan, V. A.; Kottke, T. J.; Kaufmann, S. H. J. Clin. Invest. 2002, 110, 91; Deng, C. X. Nucleic Acids Res. 2006, 34, 1416; Abraham, R. T. Genes Dev. 2001, 15, 2177]. This deficiency in the cell cycle checkpoint is important, as it increases chances for cancer cells to enter mitosis before repairing the damage. The accumulation of unrepaired DNA damage triggers mitotic catastrophe to these cells. It is believed that the treatment-induced growth inhibition by anticancer drugs is due to apoptosis, senescence and/or mitotic catastrophe [de Bruin, E. C.; Medema, J. P. Cancer Treat. Rev. 2008, 34, 737; Okada, H.; Mak, T. W. Nat. Rev. Cancer 2004, 4, 592; Vakifahmetoglu, H.; Olsson, M.; Zhivotovsky, B. Cell Death. Differ. 2008, 15, 1153].
Despite the increased understanding of the molecular events involved in the initiation and progression of breast cancer, and the influence of microenvironment on cancer cell growth, the therapeutic outcome of drugs is still far from the maximum efficiency. Currently, few treatment options for the intervention and prevention of early breast cancer (docetaxel, pacilitexal and trastuzumab) and for the advanced or metastatic breast cancer (gemcitabine, lapatinab and bevacizumab) are available [Takeda, A.; Loveman, E.; Harris, P.; Hartwell, D.; Welch, K. Health Technol Assess 2008, 12, 1]. Most of these drugs act by inducing tubulin polymerization, forming multi-polar spindles, causing DNA damage, and leading to mitotic arrest [Bollag, D. M.; McQueney, P. A.; Zhu, J.; Hensens, O.; Koupal, L.; Liesch, J.; Goetz, M.; Lazarides, E.; Woods, C. M.; Cancer Res. 1995, 55, 2325]. Since the success with existing drugs is still awaited, the new class of anti-estrogen drugs for breast cancer treatment are continuously generated and tested for longer survival with recurrence of the disease. Anti-cancer drugs, which induce DNA damage become resistant, and their therapeutic outcome becomes limited [Chuthapisith, S.; Eremin, J. M.; El-Sheemy, M.; Eremin, O. Surgeon 2006, 4, 211; Gonzalez-Angulo, A. M.; Morales-Vasquez, F.; Hortobagyi, G. N. Adv. Exp. Med. Biol. 2007, 608, 1]. Thus, there is clearly an urgent need for the development of new therapeutic treatment strategies.
Polymethoxylated phenyl rings are often found in the structure of anti-cancer agents such as steganacin [Kupchan, M. S.; Britton, R. W.; Ziegler, M. F.; Gilmore, C. J.; Restivo, R. J.; Bryan, R. F. J. Am. Chem. Soc. 1973, 95, 1335; Tomioka, K.; Ishiguro, T.; Mizuguchi, H.; Komeshima, N.; Koga, K.; Tsukagoshi, S.; Tsuruo, T.; Tashiro, T.; Tanida, S.; Kishi, T. J. Med. Chem. 1991, 34, 54], colchicines [Pohle, K.; Matthies, E.; Peters, J. E. Arch. Geschwulstforsch. 1965, 25, 17; Chen, J.; Liu, T.; Dong, X.; Hu, Y. Mini-Rev. Med. Chem. 2009, 9, 1174], podophyllotoxin [Gordaliza, M.; Castro, M. A.; Corral, J. M. M.; San Feliciano, A. Curr Pharm Des 2000, 6, 1811; You Y, J. Curr. Pharm. Des. 2005, 11, 1695], and noscapine [Ye, K.; Ke, Y.; Keshava, N.; Shanks, J.; Kapp, J. A.; Tekmal, R. R.; Petros, J.; Joshi, H. C. Proc. Natl. Acad. Sci. USA. 1998, 95, 1601].
Presented herein are methoxylated biisoquinoline compounds, which can be conveniently prepared in three steps from commercial starting materials, rendering their lead optimization process facile compared to structurally more complex natural products. Herein, we report syntheses of variously methoxylated biisoquinoline derivatives and their highly potent growth inhibitory effects on both triple-positive and triple-negative human breast cancer cell lines.